Ring Contraction Rearrangement Research Articles

Cadinane-Type Sesquiterpenoids with Cytotoxic Activity from the Infected Stems of the Semi-mangrove Hibiscus tiliaceus

Eight new cadinane sesquiterpenoids (1-8), along with two known compounds (9 and 10), were isolated from infected stems of the semi-mangrove plant, Hibiscus tiliaceus. The structures of compounds 1-8 were elucidated through the analysis of their 1D and 2D NMR and MS data, and their absolute configurations were determined by comparing their experimental and calculated ECD spectra and by single-crystal X-ray diffraction. The two confused known compounds (9 and 10) were resolved using single-crystal X-ray crystallography. Compounds 1-3 have novel norsesquiterpene carbon skeletons arising from a ring contraction rearrangement. All obtained isolates were evaluated against the HepG2 and Huh7 cell lines, and compounds 1b, 2b, 4, 6, and 8 showed cytotoxic activity toward both cell lines, with IC50 values ranging from 3.5 to 6.8 μM.

Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids.

Tropolone sesquiterpenoids (TS) are an intriguing family of biologically active fungal meroterpenoids that arise through a unique intermolecular hetero Diels–Alder (hDA) reaction between humulene and tropolones. Here, we report on the combinatorial biosynthesis of a series of unprecedented analogs of the TS pycnidione 1 and xenovulene A 2. In a systematic synthetic biology driven approach, we recombined genes from three TS biosynthetic gene clusters (pycnidione 1, xenovulene A 2 and eupenifeldin 3) in the fungal host Aspergillus oryzae NSAR1. Rational design of the reconstituted pathways granted control over the number of hDA reactions taking place, the chemical nature of the fused polyketide moiety (tropolono‐ vs. monobenzo‐pyranyl) and the degree of hydroxylation. Formation of unexpected monobenzopyranyl sesquiterpenoids was investigated using isotope‐feeding studies to reveal a new and highly unusual oxidative ring contraction rearrangement.

Synthesis and biological evaluation of steroidal derivatives bearing a small ring as vitamin D receptor agonists

A novel series of 3-ketolithocholic acid derivatives as well as estrone derivatives bearing a small ring for the conformational fixation of the side chain were synthesized by using a catalytic [2+2] cycloaddition and a ring-contraction rearrangement. The steroidal derivatives were evaluated for transcriptional activation of vitamin D receptor by luciferase reporter assays. Among them, two estrone derivatives showed a higher efficacy of the transactivation of vitamin D receptor than 3-ketolithocholic acid, and the small ring moieties were found to be important for the efficacy.

Recent Developments in Total Syntheses of Cephalosporolides, Penisporolides, and Ascospiroketals.

The possible biogenetic connection of the 10-membered lactone (decanolide) and the tricyclic [5,5]-spiroacetal-cis-fused-γ-lactone (SAFL) natural products was proposed by Hanson in 1985. Mimicking such biosynthetic hypothesis led us to develop a general synthetic strategy for the total syntheses of both decanolide-type cephalosporolides and SAFL-type natural products. This biomimetic strategy features two key transformations: i) oxidative ring expansion of bicyclic β-hydroxy tetrahydropyrans to the decanolides and ii) ring contraction rearrangement of the decanolides to the tricyclic SAFLs. In particular, the phenol derivatives are exploited as the starting materials for the decanolides and then the SAFLs. The successful biomimetic total synthesis allows us to revise the structures and biosynthetic hypothesis of several natural products, along with development of an NMR analysis method for determination of the relative stereochemistry of SAFL-type compounds. In addition, this account will summarize recent synthetic work by other research groups.

Total Synthesis of Purported Cephalosporolides H and I, Penisporolide B, and Their Stereoisomers.

Development of a unified, bioinspired synthetic strategy to access four possible diastereomers of unique 2,2-dimethyl-[5,5]-spiroacetal-cis-fused-γ-lactone (Me2SAFL) is reported, featuring pyridinium chlorochromate (PCC)-promoted oxidative ring expansion of β-hydroxy cyclic ethers and dehydrative ring-contraction rearrangement of 10-membered lactones. Synthetic utility of this strategy was demonstrated by total syntheses of 12 Me2SAFLs, corresponding to the purported cephalosporolide H (CesH), cephalosporolide I (CesI), and penisporolide B (PenB) and their possible diastereomers. Comprehensive NMR data analysis suggested that the tricyclic Me2SAFL core of CesH, CesI, and PenB should be revised to the same relative (3R*, 4R*, 6S*, 9R*) configuration and that the side chains required an unknown constitutional structure revision.

Asymmetric Total Syntheses of ent-Ascospiroketals A and B.

A new hypothetic biosynthesis of the tricyclic spiroketal core of ascospiroketals A and B is proposed, which guided the development of a novel synthetic strategy for the asymmetric total synthesis of ent-ascospiroketals A and B. The synthesis features an efficient ring contraction rearrangement of the 10-membered lactone to the tricyclic spiroketal cis-fused γ-lactone core, which served as the common intermediate for the synthesis of both ent-ascospiroketals A and B through the Stille coupling reaction at the final step. In addition, seven diastereomers were prepared to conclusively confirm the structure of ent-ascospiroketal B.

Synthesis of steroidal derivatives bearing a small ring using a catalytic [2+2] cycloaddition and a ring-contraction rearrangement

Fixing conformation by introducing a ring structure is a common strategy in drug development. We demonstrate a synthesis that installs a small carbocyclic ring as a structurally-rigid unit in drug lead compounds. Both trans- and cis-cyclobutane rings were constructed in excellent selectivities by controlling the reaction temperature of an EtAlCl2-catalyzed [2+2] cycloaddition between a silyl enol ether and an α,β-unsaturated ester. Spirocyclopropane rings were stereospecifically formed by our previously reported ring-contraction rearrangement of fused cyclobutanols. This strategy allowed stereodivergent access to a new class of steroidal derivatives bearing a small ring.

Novel synthesis of benzimidazole by Ring Contraction Rearrangement of benzodiazepine

Condensation of substituted aromatic ketones (acetophenone) and substituted aldehydes give unsaturated ketones 14 (chalcones) which react with o-phenylenediamine 7 to afford the corresponding benzodiazepines 15 . Treatments of benzodiazepines under basic conditions give benzimidazole derivatives. Structures of all synthesized compounds have been characterized by their NMR and mass spectral data. Keywords: N’-Thioacylamidines, Chalcone, o-phenylenediamine, benzodiazepine, benzimidazole.

Cephalosporolide B Serving as a Versatile Synthetic Precursor: Asymmetric Biomimetic Total Syntheses of Cephalosporolides C, E, F, G, and (4-OMe-)G

Cephalosporolide B (Ces-B) was efficiently synthesized and exploited for the first time as a versatile biomimetic synthetic precursor for the chemical syntheses of not only cephalosporolides C, G, and (4-OMe-) G via a challenging diastereoselective oxa-Michael addition but also the structurally unprecedented cephalosporolides E and F via a novel biomimetic ring-contraction rearrangement. These findings provide the first direct chemical evidence that Ces-B may be the true biosynthetic precursor of cephalosporolides.

PdCl2-Catalyzed Oxidative Cycloisomerization of 3-Cyclopropylideneprop-2-en-1-ones

A novel PdCl(2)-catalyzed oxidative cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones, providing a facile synthesis of highly strained functionalized 2-alkylidenecyclobutanones via furan-fused cyclobutene intermediates, is reported. An interesting route to 2(3H)-furanones with a spiro-cyclopropane unit from the obtained 2-alkylidenecyclobutanones via a ring-contraction rearrangement reaction is also realized.

Unexpected spontaneous ring-contraction rearrangement of trifluoromethylated 1,2-oxazine N-oxides to 1-pyrroline N-oxides

6-Amino-4-trifluoromethyl-5,6-dihydro-4 H -1,2-oxazine 2-oxides undergo spontaneous rearrangement into 4-amino-2-hydroxy-4-trifluoromethyl-3,4-dihydro-2 H -pyrrole 1-oxides.

ChemInform Abstract: Stereodefined Ring Contraction—Rearrangement of Thiocoumarins to New Fused Benzo[b]thiophene Derivatives.

AbstractMuenchnone (II) undergoes title ring contraction—rearrangement reaction with thiocoumarins having an electron‐withdrawing group at position 3 to give stereodefined fused polycyclic thienopyrroles.

ChemInform Abstract: A Novel Rearrangement in the System 3‐[Aryl(chloro)methyl]quinoxalin‐2(1H)‐one—α‐Picoline as a Simple and Efficient Route to Indolizin‐2‐ylbenzimidazoles.

A reaction of 3-(α-chlorobenzyl)quinoxalin-2(1 H)-one with α-picoline gives 2-(3-phenyl-indolizin-2-yl)benzimidazole as a result of a ring-contracting rearrangement involving the fragment C(2)—C(3)—C(Cl)Ph of the quinoxaline system and the fragment N=CH—Me of the α-picoline system. Possible pathways of this reaction are discussed.

ChemInform Abstract: Stereocontrolled Synthesis of Spiro[n.2]alkenes by Ring Contraction of Fused‐Cyclobutanols.

AbstractThe present newly developed unusual ring contraction rearrangement leads to spirocyclopropanes from fused cyclobutanols.

Stereocontrolled Synthesis of Spiro[n.2]alkenes by Ring Contraction of Fused‐Cyclobutanols

An unusual ring-contraction rearrangement to give spirocyclopropanes from fused cyclobutanols (see scheme) has been developed. It is found that the strain energy of the substrates derived from an additional fused ring and the stereoelectronic effect of the migrating sigma bond are important factors. It is noteworthy that the rearrangement proceeds in a stereospecific manner. Moreover, the method provides a spiro(cyclopropane-indane) framework from tricyclo[6.3.0.02,5]undecane, which corresponds to illudane and the protoilludane skeleton.

A novel rearrangement in the system 3-[aryl(chloro)methyl]quinoxalin-2(1H)-one— α-picoline as a simple and efficient route to indolizin-2-ylbenzimidazoles

A reaction of 3-(α-chlorobenzyl)quinoxalin-2(1 H)-one with α-picoline gives 2-(3-phenyl-indolizin-2-yl)benzimidazole as a result of a ring-contracting rearrangement involving the fragment C(2)—C(3)—C(Cl)Ph of the quinoxaline system and the fragment N=CH—Me of the α-picoline system. Possible pathways of this reaction are discussed.

Theoretical Study of the AlEt3-Promoted Tandem Reductive Rearrangement of Epoxides

The AlEt3-promoted tandem reductive rearrangement reactions of epoxides was studied at B3LYP/6-31G(d,p) level. For the model compound -hydroxy epoxides, two possible reaction pathways I and II were calculated. The main difference is the order of ethylene release and six- to five-member ring rearrangement. The ring contraction rearrangement in pathway I is the first step and this step is the rate controlling step with a free energy barrier of 116.62 kJ/mol. For pathway II, the ethylene release occurs first, and is followed by a six-member ring opening reaction which is the rate controlling step, and the barrier is 251.38 kJ/mol. The reason for such high barrier is that the ethylene release results in the following reaction being more difficult. The results show that pathway I (CC rearrangement and then ethylene release) is more favorable, which is consistent with experimental results.

New Strategy for the Construction of Epoxy-Bridged Tetrahydropyran Frameworks from Trioxane Precursors: Application to a Concise Synthesis of a Riesling Acetal

A simple one-pot method to prepare dioxabicyclo[2.2.1] heptane derivatives, from readily available 1,2,4-trioxane frameworks, under catalytic hydrogenation conditions over a platinum surface is reported. The overall transformation involves the hydrogenation of the double bond and a ring contraction rearrangement that presumably proceeds via a hydrogenolytic cleavage of the O-O bond and subsequent intramolecular ketalization. The strategy was successfully applied to the synthesis of a Riesling acetal.

The fragmentation mechanism of β-(N-alkyl/arylamino)-α,β-unsaturated carboxylates under electrospray ionization conditions

The positive ion mass spectrometric behavior of six beta-(N-alkyl/arylamino)-alpha,beta-unsaturated carboxylates, alpha-(1-alkyl/arylaminoethylidene)-gamma-lactones, has been studied under electrospray ionization conditions. Their fragmentation pathways are described and supported by tandem mass spectrometry. The protonated compounds are apt to eliminate a water, and a water plus a oxacyclopent-2-yne molecule. Some of the compounds show a tendency to undergo a four-membered ring contraction rearrangement to lose a carbon dioxide. The fragmentation patterns of these compounds exhibit a strong substituent dependency.

Synthesis of 1,4‐Benzodiazepine‐3,5‐diones.

AbstractFor Abstract see ChemInform Abstract in Full Text.